Cells reprogrammed to mend a broken heart

Fixing a broken heart has never been easy, but damaged mice hearts can now be repaired by transforming injured cells into healthy beating muscle cells. The approach sidesteps the use of stem cells and could lead to new heart treatments.

After a heart attack, cells called fibroblasts flock to damaged areas where they deposit collagen. Because fibroblasts do not contract like heart muscle cells – known as cardiomyocytes – the heart’s overall pumping ability in this area is weakened, leading to a less efficient heart.

Victor Dzau at Duke University in Durham, North Carolina, has now shown that microRNAs – small molecules that act as “master switches” for a large number of genes – can transform fibroblasts into muscle cells.

In cultured mouse fibroblasts, a combination of four microRNAs delivered by viruses transformed 4 per cent of the cells into cardiomyocytes. When a drug called Jak Inhibitor I was added to the cocktail, almost 30 per cent of the cells were transformed.

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Same difference

The transformed cardiomyocytes showed the same properties as native cardiomyocytes, including an altered anatomy and weak contractions. Dzau found a similar response after injecting the viruses into mice with heart damage. “The new cardiomyocytes totally integrated in the heart. You can’t tell the cells apart,” Dzau says.

The approach may be a better alternative to using stem cells that have also been shown to restore heart function. Embryonic stem cells face ethical challenges, while manipulating adult stem cells is a technically complex process.

Direct reprogramming of fibroblasts to heart muscle in mice was also reported last week by Deepak Srivastava at University of California, San Francisco (Nature, DOI&colon; 10.1038/nature/11044). Srivastava’s group used transcription factors – proteins that switch genes on and off – rather than microRNAs to genetically change the cells’ identities.

In the future the two approaches could be used together to increase the number of cells converted. “I think the microRNA work is intriguing and supports the paradigm that the abundant pool of non-muscle cells in the heart can be converted into new cardiac muscle,” says Srivastava. “The microRNAs may improve the efficiency of the conversion together with the previously described factors from our group.”

“Direct reprogramming is the most exciting thing in cell therapy. Now there are two ways that you can actually do it in an animal – and that sets the stage for human therapeutics,” Dzau says.